Azeliragon + Chemoradiotherapy for Glioblastoma

Recruiting at 1 trial location

Overseen By Jiayi Huang, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Washington University School of Medicine

Must be taking: Temozolomide

Must not be taking: CYP 2C8 inhibitors

Disqualifiers: Prior cranial RT, IDH mutation, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment approach for glioblastoma, an aggressive brain cancer. It combines azeliragon, a drug that may help immune cells fight tumors, with standard radiation therapy and chemotherapy (temozolomide). Researchers aim to determine if this combination can better control the tumor by enhancing the body's immune response. The trial seeks participants diagnosed with glioblastoma who have a visible tumor after surgery and plan to undergo more surgery or laser treatment. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this novel therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take CYP 2C8 inhibitors within 2 weeks before joining the study. It's best to discuss your current medications with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that azeliragon, when combined with standard radiation therapy (RT) and the drug temozolomide (TMZ), is safe for treating glioblastoma, a type of brain cancer. Patients generally tolerate the starting doses well without severe side effects. Although rare, some serious side effects, such as paralysis and brain inflammation, have been reported. Overall, current research indicates that the combination of azeliragon with RT and TMZ is well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard glioblastoma treatment that typically involves radiation and chemotherapy with temozolomide (TMZ), the investigational approach includes azeliragon, which is exciting because it targets a different pathway. Azeliragon works by modulating the receptor for advanced glycation end-products (RAGE), potentially reducing inflammation and inhibiting tumor growth. This novel mechanism of action offers hope for enhanced effectiveness, potentially improving patient outcomes by tackling the disease from a new angle. Researchers are eager to see if combining azeliragon with traditional treatments could lead to better results than current options alone.

What evidence suggests that this trial's treatments could be effective for glioblastoma?

Research has shown that azeliragon, a drug that blocks certain harmful proteins, may help treat glioblastoma (GBM) when combined with radiation therapy. In studies with mice, this combination greatly improved survival rates compared to radiation alone. Azeliragon works by reducing cells that weaken the immune system and boosting T-cells, which are crucial for fighting tumors. Although more research is needed, early results suggest it could enhance the effectiveness of standard treatments like radiation and the chemotherapy drug temozolomide. This trial will explore two treatment arms: one where participants receive neoadjuvant radiation therapy and temozolomide followed by surgery and adjuvant temozolomide with azeliragon, and another where participants receive azeliragon in addition to neoadjuvant radiation therapy and temozolomide, followed by surgery and adjuvant temozolomide with azeliragon. Ongoing studies are investigating this potential in human patients. ^{1 3 4 5 6}

Who Is on the Research Team?

Jiayi Huang, M.D.

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

This trial is for patients with a new diagnosis of glioblastoma, which is an aggressive type of brain tumor. Participants should be suitable for surgery or laser interstitial thermal therapy (LITT), and ready to undergo radiation therapy and take the drug Temozolomide. Specific inclusion and exclusion criteria details are not provided.

Inclusion Criteria

I am willing to undergo surgery to remove or treat the tumor after chemoradiotherapy.

I can care for myself but may need occasional help.

Females of childbearing potential must be willing to use an acceptable method of birth control during the trial and for 6 months after the last administration of azeliragon

Exclusion Criteria

My cancer has spread to the lining of the brain or other areas.

Patients with concurrent participation in another interventional clinical trial or use of another investigational agent within 30 days prior to study entry

I haven't taken CYP 2C8 inhibitors in the last 2 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Chemoradiotherapy

Participants receive fractionated radiation therapy (RT) to 60 Gy in 30 daily fractions with concurrent Temozolomide (TMZ) and, in some arms, Azeliragon

6 weeks

Surgery or LITT

Participants undergo planned surgery of either resection or Laser Interstitial Thermal Therapy (LITT) 1 month after completion of RT

1 month

Adjuvant Therapy

Participants receive adjuvant Temozolomide (TMZ) and Azeliragon for up to 6 months

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Azeliragon
• Radiation therapy

Trial Overview The study tests if adding Azeliragon, a drug that inhibits RAGE (a receptor involved in inflammation), to standard treatment with radiation and Temozolomide can make the immune system better at controlling tumor growth in glioblastoma patients.

How Is the Trial Designed?

Group I: Arm 2: Neoadjuvant RT, Temozolomide (TMZ) & Azeliragon + Surgery or LITT + Adjuvant TMZ & Azeliragon Experimental Treatment 4 Interventions

RT will consist of fractionated RT to 60 Gy in 30 daily fractions administered per standard of care RTOG approach. Concurrent TMZ during RT will be self-administered by mouth (PO) as per standard of care. Patients will receive azeliragon as well. Azeliragon is self-administered PO. Azeliragon dosing will consist of 6 days of a loading dose of 30 mg twice per day starting on day -6, followed by 20 mg daily starting on the Day 1. Concurrent RT and TMZ start on Day 1. Azeliragon should continue until the day before planned surgical procedure. 1 month after completion of RT, patient will proceed with planned surgery of either resection or LITT. Patients will then receive adjuvant TMZ and azeliragon for up to 6 months. Patient should start with the loading dose 30 mg BID for 6 days before the start of adjuvant TMZ. After 6 days, azeliragon 20 mg once daily should be continued in combination with TMZ.

Group II: Arm 1: Neoadjuvant RT and Temozolomide (TMZ) + Surgery or LITT + Adjuvant TMZ & Azeliragon Active Control 4 Interventions

Radiation therapy (RT) will consist of fractionated RT to 60 Gy in 30 daily fractions administered per standard of care RTOG approach. Concurrent TMZ during RT will be self-administered by mouth (PO) as per standard of care. 1 month after completion of RT, patient will proceed with planned surgery of either resection or LITT. Patients will then receive adjuvant TMZ and azeliragon for up to 6 months. Patient should start with the loading dose 30 mg BID for 6 days before the start of adjuvant TMZ. After 6 days, azeliragon 20 mg once daily should be continued in combination with TMZ.

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Cantex Pharmaceuticals

Industry Sponsor

Trials

14

Recruited

390+

Published Research Related to This Trial

In a phase II trial involving 265 patients with newly diagnosed glioblastoma and unmethylated MGMT promoter, the standard cilengitide regimen showed a median overall survival of 16.3 months, which was significantly better than the control arm's 13.4 months.

Both cilengitide regimens were well tolerated, but the study's inconsistent survival outcomes and limited sample size made it difficult to draw firm conclusions about the clinical efficacy of cilengitide in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study. Nabors, LB., Fink, KL., Mikkelsen, T., et al.[2022]

Temozolomide (TMZ) was found to effectively radiosensitize two out of three human glioblastoma multiforme (GBM) cell lines when combined with single-dose gamma-irradiation, indicating its potential to enhance the effectiveness of radiation therapy.

In a study involving three genetically characterized GBM cell lines, TMZ demonstrated an additive effect with fractionated irradiation, particularly showing a significant reduction in surviving cells in the AMC 3046 cell line, suggesting that TMZ can improve treatment outcomes for certain GBM patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential radiosensitizing potential of temozolomide in MGMT promoter methylated glioblastoma multiforme cell lines. van Nifterik, KA., van den Berg, J., Stalpers, LJ., et al.[2018]

In a study involving 16 patients with newly diagnosed glioblastoma multiforme, the combination of intensity-modulated radiotherapy (IMRT) and temozolomide (TMZ) was found to be tolerable, with a median survival of 16.2 months, indicating potential efficacy in this patient population.

The study demonstrated that escalating the IMRT dose to 6 Gy per fraction was achievable without reaching the maximal tolerated dose, suggesting that higher doses may be safely administered in selected patients with smaller tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of hypofractionated intensity-modulated radiotherapy with temozolomide chemotherapy for patients with newly diagnosed glioblastoma multiforme. Chen, C., Damek, D., Gaspar, LE., et al.[2018]

In a study of 126 newly diagnosed glioblastoma patients, both standard dose radiotherapy (SDRT) and escalated dose radiotherapy (EDRT) combined with temozolomide (TMZ) showed similar overall survival (OS) and local progression-free survival (LPFS), with no statistically significant differences between the two treatments.

While the EDRT group had a median OS of 22 months compared to 14.9 months for SDRT, this difference was not statistically significant, indicating that further research with larger populations is needed to determine the true efficacy of EDRT in combination with TMZ.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective comparison of standard and escalated doses of radiotherapy in newly diagnosed glioblastoma patients treated with concurrent and adjuvant temozolomide. Guler, OC., Yıldırım, BA., Önal, C., et al.[2019]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.2069

Azeliragon, a RAGE inhibitor, in combination with ... Our hypothesis was that azeliragon may enhance the efficacy of Stupp regimen in newly diagnosed GBM. Methods: CAN-201 NDG is an open-label, ...

2. academic.oup.com academic.oup.com/neuro-oncology/article/26/Supplement_8/viii91/7890165

CTIM-26. PHASE II STUDY OF AZELIRAGON IN ... The study hypothesizes that azeliragon and RT will improve median progression-free survival (PFS) to 9.7 months compared to historical control ...

3. targetedonc.com targetedonc.com/view/fda-okays-phase-2-study-of-azeliragon-for-patients-with-glioblastoma

FDA Okays Phase 2 Study of Azeliragon for Patients With ... Currently, the median survival is 15-18 months for patients with GBM after their diagnosis. With the 5-year survival also less than 10%, there ...

4. annalsofoncology.org annalsofoncology.org/article/S0923-7534(24)02041-6/fulltext

452MO Early experience with azeliragon, a RAGE inhibitor, ... Here we focus on the safety data from the first two dose levels completed. Results. From Oct 2023 to Mar 2024, 12 pts were included, 6 in both L1 and L2. The ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.e14056

A preclinical study to evaluate the combination of ... Results: GBM tumor-bearing mice (GL261 & CT2A) treated with RT plus azeliragon had significantly improved survival when compared to RT alone or ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05635734

Azeliragon and Chemoradiotherapy in Newly Diagnosed ... This is an open label study to determine the safety and preliminary evidence of a therapeutic effect of azeliragon in patients with newly diagnosed glioblastoma ...